Antrum Mucosal Protein (AMP)-18 (also called gastrokine-1) is an 18 kDa protein expressed in mucosal epithelial cells of the gastric antrum. Within stomach cells the protein is found in vesicles together with mucins just under the lumenal cell surface. AMP-18 is secreted onto the stomach lining as a component of the viscoelastic gel that coats the mucosal surface. The native protein and a 21-mer peptide comprising amino acids 77-97 (AMP77-97 peptide) both function as mitogens and motogens for gastrointestinal (GI) epithelial cells. AMP77-97 peptide also acts on the tight junctions (TJs) (FIG. 1) that hold GI mucosal epithelial cells together by preventing the loss of specific proteins such as occludin and ZO-1 after injury, and by facilitating assembly of TJ proteins to repair mucosal barrier function and structure which could protect the gut against the entry of bacteria, their toxins, and other potentially injurious molecules that reside in the gut lumen.
Mucositis is an inflammatory and ulcerative injury of the mouth, throat or GI tract most commonly caused by chemo- or radiation therapy for cancer. This disease has its onset when chemotherapy or radiation disrupts the mucosal surface of the mouth and other portions of the GI tract, affecting both the epithelial layer and the underlying connective tissue. In severe cases, oral mucositis can be extremely painful, preventing the patient from eating, and requiring hospitalization for hydration, narcotics for pain, and/or total parenteral nutrition. Pain resulting from mucositis is so severe that it is often cited by cancer patients as the primary reason for discontinuing treatment. Patients suffering from mucositis may feel as if they were drinking scalding hot water and scraping the inside of their mouth with coarse sand paper followed by running their tongue over a cheese grater. Mucositis can also be life-threatening because oral ulcerations can permit the entry of bacteria into the bloodstream, a situation which can be fatal in a patient already immune-compromised by treatment for cancer.
Overall, mucositis affects 15-40 percent of patients receiving standard-dose chemotherapy and 76-100 percent of patients receiving higher doses of chemotherapy for bone marrow transplantation (FIG. 7). Mucositis also affects virtually all patients receiving radiation therapy for head and neck cancer, as well as patients receiving radiation along the GI tract. For example, esophagitis (or esophageal mucositis) is a major complication of chemoradiation therapy in patients with non-small cell lung cancer that produces significant morbidity and results in treatment interruptions. Mucositis afflicts over 400,000 patients a year in the US, and the incidence is growing as the need for radiation and chemotherapy treatments grows. This represents a potential annual market of greater than $800 million in the US.
Treatment of oral mucositis is a significant unmet medical need. Current treatment strategies are primarily palliative and include mucosal coating mixtures that may contain topical anesthetics and antibiotics to prevent infection. These treatments provide little benefit, and do not speed healing or decrease severity of mucositis. The only currently approved therapeutic for mucositis is Kepivance™ which is the known mitogenic protein keratinocyte growth factor (KGF) that must be administered intravenously. Kepivance™ is approved for a single indication which comprises only 4% of the total mucositis population, i.e., treatment of mucositis resulting from pre-conditioning regimens (chemotherapy and radiation) in stem-cell transplant patients.